Abstract
Background: KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and methods: Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined. Results: KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<. 0.001), smoking-associated G>T transversions (73% versus 27%; p<. 0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<. 0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion: In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.
Original language | English (US) |
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Pages (from-to) | 163-167 |
Number of pages | 5 |
Journal | Lung Cancer |
Volume | 83 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2014 |
Keywords
- Colorectal cancer (CRC)
- EGFR-targeted therapy
- KRAS mutations
- Molecular genetics
- Non-small-cell lung cancer (NSCLC)
- Personalized medicine
- Predictive biomarkers
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
- Cancer Research